Planning to introduce novel tuberculosis vaccines in high burden settings: how could this be done?
Authors: Mark F Cotton, Helena Rabie
Journal: The Lancet Global Health (2023)

Tuberculosis is a major cause of death and morbidity globally. The STOP TB partnership began a global plan to address tuberculosis and its complexities in 2008, with an emphasis on the need for strong health systems.1WHOGlobal tuberculosis control: surveillance, planning, financing: WHO report 2008. World Health Organization, Geneva2008Google Scholar The WHO-led End TB strategy, which was announced in 2015, included a roadmap to eliminate tuberculosis by 2035,2WHOUNAIDSGlobal AIDS response progress reporting. World Health Organization, Geneva2015Google Scholar and an effective vaccine was a key component of this strategy. Although tuberculosis vaccine research began in earnest in the 1990s, a strategic blueprint for tuberculosis vaccine development beyond the BCG vaccine was released in 2012. Recognising that tuberculosis is spread by adults and adolescents from approximately 10 years of age and that HIV increases vulnerability, these groups are important target populations for vaccination. Because of the time taken to develop confirmed tuberculosis disease after infection, other endpoints such as Mycobacterium tuberculosis infection status rather than tuberculosis disease were developed: for example, interferon g release to M tuberculosis antigens. WHO established criteria for introducing new tuberculosis vaccines in 2018, supporting efficacy of at least 50% in adults and adolescents, although acknowledging that a slightly less efficacious vaccine could be beneficial in this population. For infants, a vaccine should be either better than BCG or at least 80% effective in preventing tuberculosis.3WHOWHO preferred product characteristics for new tuberculosis vaccines. World Health Organization, Geneva2018Google Scholar Two tuberculosis vaccine studies show promise. Repeat BCG vaccination was 45·4% efficacious in preventing sustained interferon g release in adolescents without evidence of infection in a high burden setting.4Nemes E Geldenhuys H Rozot V et al.Prevention of M tuberculosis infection with H4:IC31 vaccine or BCG revaccination.N Engl J Med. 2018; 379: 138-149Crossref PubMed Scopus (414) Google Scholar In adults, the subunit M72/AS01 vaccine had 49·7% efficacy in preventing progression of M tuberculosis infection to disease.5Tait DR Hatherill M Van Der Meeren O et al.Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis.N Engl J Med. 2019; 381: 2429-2439Crossref PubMed Scopus (245) Google Scholar Three vaccines are in adult phase 3 studies. These include VPM1002 (a recombinant BCG vaccine), inactivated Mycobacteriumindicus pranii, and GamTBVac (an adjuvanted subunit vaccine).6Dockrell HM McShane H Tuberculosis vaccines in the era of COVID-19—what is taking us so long?.EBioMedicine. 2022; 79103993Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar VPM1002 and MTBVAC—a live M tuberculosis vaccine from which pathogenic genes have been removed—are being studied in infants. Considering these developments, Clark and colleagues7Clark RA Mukandavire C Portnoy A et al.The impact of alternative delivery strategies for novel tuberculosis vaccines in low-income and middle-income countries: a modelling study.Lancet Glob Health. 2023; 11: e546-e555Summary Full Text Full Text PDF Scopus (6) Google Scholar conducted a modelling study to explore implementation strategies for an effective tuberculosis vaccine to all age groups. The outcome was measured by death and disease averted by 2050 in 105 lower-income and middle-income countries (LMICs). Factors considered included how previous new vaccines were introduced, tuberculosis burden, regulatory barriers, and means of procurement. Base-case implementation included routine vaccination of children aged 9 years and a one-time vaccination campaign to be scaled up over 5 years for those 10 years and older. In an accelerated approach, instant scale-up replaced gradual implementation of the base-case. In the routine-only model, those aged 9 years were assumed to be given routine vaccinations, with no catch-up campaign for those aged 10 years and older. All implementation strategies will prevent death from and incidence of tuberculosis disease, but more deaths and cases will be prevented with rapid scale-up. The same group also published a cost-effectiveness model for the same LMICs, estimating a saving of US$283 billion to $474 billion by 2050, especially in countries with high tuberculosis burdens.8Portnoy A Clark RA Quaife M et al.The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: a modeling study.PLoS Med. 2023; 20e1004155Crossref PubMed Scopus (6) Google Scholar Replacing the current BCG vaccination at birth is logistically feasible, provided that the new vaccine is cost-effective within countries and production can be appropriately upscaled. The main question is how tuberculosis vaccine programmes will be implemented in adolescents and adults from LMICs. Evidence from previous vaccine implementation for pneumococcal disease, influenza, and herpes zoster is not encouraging. In 2017, only 38% of WHO member states reported a national adult vaccination policy for influenza, 27% for pneumococcal disease, and 3% for herpes zoster.9Sauer M Vasudevan P Meghani A et al.Situational assessment of adult vaccine preventable disease and the potential for immunization advocacy and policy in low- and middle-income countries.Vaccine. 2021; 39: 1556-1564Crossref PubMed Scopus (15) Google Scholar The situation in LMICs for human papillomavirus immunisation targeting mainly female children and adolescents was better: the coverage obtained was almost 62%, and it was higher in countries with specific programmes, which is useful information for rolling out novel tuberculosis vaccines. COVID-19 immunisation programmes offer a model for adult immunisation: all countries initiated adult immunisation programmes and tracked roll-out. Upper-middle-income countries, including those with a high tuberculosis burden such as South Africa, perform similarly to high-income countries for vaccine coverage, with LMICs lagging but improving.10Our World in DataCOVID-19 vaccine doses administered per 100 people, by income group.https://ourworldindata.org/grapher/cumulative-covid-vaccinations-income-groupDate: Jan 30, 2023Date accessed: January 31, 2023Google Scholar An additional question is affordability and accessibility of vaccination programmes. Would countries be able to budget for purchase and implementation and would pre-ordering of supplies be need to ensure access, as for COVID-19 immunisation? Introducing effective novel tuberculosis vaccines will have major benefits, increasing with commitment within individual countries. Tuberculosis vaccines represent a major opportunity to develop adult and adolescent immunisation programmes, similar to those for children. Paradoxically, although COVID-19 severely affected tuberculosis programmes globally, lessons learned from COVID-19 immunisation programmes, if well planned and communicated, could be a major factor in actually ending the tuberculosis pandemic. MFC reports payment from Vakzine Project Management and the Serum Institute of India to his institution as an investigator for the VPM1002 infant trials and from Biofabri to his institution as an investigator for the MTBVAC infant trials, in addition to financial support from Biofabri for attending the start up meetings for both trials. HR reports membership on the MTBVAC study team, and membership on Data Safety Monitoring Boards for the EMPIRICAL study and on steering committee for the TB Speed study, and membership of the FAMCRU board (but receiving no payment for any of these roles). The impact of alternative delivery strategies for novel tuberculosis vaccines in low-income and middle-income countries: a modelling studyOur results suggest novel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a one-off vaccination campaign will be crucial for rapid impact. Accelerated introduction—at a pace similar to that seen for COVID-19 vaccines—would increase the number of lives saved before 2050 by around 60%. Investment is required to support vaccine development, manufacturing, prompt introduction, and scale-up. Full-Text PDF Open Access